Controlled delivery of active agents

ABSTRACT

Controlled release of active agents from sustained release push delivery devices having high drug loading are described wherein residual drug content in the device is minimized by the utilization of a flow-promoting layer between a semi-permeable wall and drug layer comprising the device.

CONTROLLED DELIVERY OF ACTIVE AGENTS

[0001] This application claims the priority of provisional applicationSerial No. 60/106,739, filed Nov. 2, 1998, which is incorporated hereinby reference.

FIELD OF THE INVENTION

[0002] This invention pertains to the controlled delivery ofpharmaceutical agents and dosage forms therefor. In particular, theinvention is directed to improved methods, dosage forms and devices forthe substantially complete release of active agents from dosage formshaving an expandable push layer and a drug layer that is to be dispensedto the environment of use.

BACKGROUND OF THE INVENTION

[0003] Certain drugs may have to be delivered in large doses, sometimesseveral times per day, to achieve a desired therapeutic effect. Whilelarge daily doses of drug may be administered by multiple dosingthroughout the day, multiple dosing regimens are often not preferredbecause of patient compliance problems, potential side effects and thedangers of overdosing. Accordingly, there has been a movement toonce-a-day or twice-a-day dosing regimens when possible, even when thereis a need for large doses of drug to be delivered over a prolongedperiod, for example 12 hours to 24 hours, as the case may be.

[0004] High ranges of daily dosing may require drug loading in drugcompositions of the dosage forms to be as much as 20% to 90% or more ofthe overall weight of the composition. Such loading requirements maypresent problems in formulating compositions and fabricating dosageforms that are suitable for oral administration and can be swallowedwithout undue difficulty. High drug loading may present even greaterproblems when formulating dosage forms that are to be administered alimited number of times per day, such as for once-a-day dosing, becauseof the large unit dosage form required.

[0005] Various devices and methods have been described having intendedutility with respect to applications with high drug loading. Forexample, U.S. Pat. Nos. 4,892,778 and 4,940,465, which are incorporatedherein by reference, describe dispensers for delivering a beneficialagent to an environment of use that include a semipermeable walldefining a compartment containing a layer of expandable material thatpushes a drug layer out of the compartment formed by the wall. The exitorifice in the device is substantially the same diameter as the innerdiameter of the compartment formed by the wall.

[0006] U.S. Pat. No. 4,915,949, which is incorporated herein byreference, describes a dispenser for delivering a beneficial agent to anenvironment of use that includes a semipermeable wall containing a layerof expandable material that pushes a drug layer out of the compartmentformed by the wall. The drug layer contains discrete tiny pillsdispersed in a carrier. The exit orifice in the device is substantiallythe same diameter as the inner diameter of the compartment formed by thewall.

[0007] U.S. Pat. No. 5,126,142, which is incorporated herein byreference, describes a device for delivering an ionophore to livestockthat includes a semipermeable housing in which a composition containingthe ionophore and a carrier and an expandable hydrophilic layer islocated, along with an additional element that imparts sufficientdensity to the device to retain it in the rumen-reticular sac of aruminant animal. The ionophore and carrier are present in a dry stateduring storage and the composition changes to a dispensable, fluid-likestate when it is in contact with the fluid environment of use. A numberof different exit arrangements are described, including a plurality ofholes in the end of the device and a single exit of varying diameter tocontrol the amount of drug released per unit time due to diffusion andosmotic pumping.

[0008] Other devices in which the drug composition is delivered as aslurry, suspension or solution from a small exit orifice by the actionof an expandable layer are described in U.S. Pat. Nos. 5,660,861,5,633,011; 5,190,765; 5,252,338; 5,620,705; 4,931,285; 5,006,346;5,024,842; and 5,160,743. Typical devices include an expandable pushlayer and a drug layer surrounded by a semipermeable membrane. Incertain instances, the drug layer is provided with a subcoat to protectthe drug composition in those portions of the gastrointestinal tracthaving acidic pH, to delay release of the drug composition to theenvironment of use or to form an annealed coating in conjunction withthe semipermeable membrane. However, such devices generally are not wellsuited as dosage forms for high drug loading due to size requirementsnecessary to accommodate large amounts of drug in a slurry, suspensionor solution, and the need to have an oral dosage form conveniently sizedso that it can be swallowed.

[0009] Another dosage form is disclosed in U.S. Pat. 5,536,507 thatdescribes a three component pharmaceutical formulation that utilizes,inter alia, a pH sensitive polymer, optionally including an osmoticagent, that will swell in the higher pH regions of the lower portion ofthe small intestine and the large intestine to release drug in thoseenvironments. Additional components of the dosage form include a delayedrelease coating and an enteric coating to provide a dosage form thatreleases very little, if any, of the drug in the stomach, a relativelyminimal amount in the small intestine and reportedly about 85% or morein the large intestine. Such a dosage form provides a widely varyingtime- release of drug after administration that may not begin for 1-3hours until the dosage form has passed from the stomach and anadditional 3 hours or more for the dosage form to pass into the largeintestine.

[0010] U.S. Pat. 5,169,638 describes a buoyant controlled releasepharmaceutical powder formulation to be filled into capsules that uses apH dependent polymer formed from alginic acid and hydroxypropylmethylcellulose to release pharmaceuticals at a controlled rate. It appearsfrom the disclosure that the capsule formulation was intended to mimicthe characteristics of a tableted formulation.

[0011] In the case of high drug loading, it is often preferable that alarge orifice, from about 50%-100% of the inner diameter of the drugcompartment, is provided in the dispensing device so that the drug layercan be dispensed in a non-fluid state. When exposed to the environmentof use, drug is released from the drug layer by erosion and diffusion. Acommon problem associated with the release of drug from prior art dosageforms in which the drug layer is dispensed from the delivery device in adry state is that a residual amount of drug often is left in the deviceand not released to the subject. Upwards of 20-30% of the drug loadingof the composition may remain in the device without being released. Inorder to compensate for that deficiency, prior art methods haveroutinely provided for overloading of drug such that the required amountis delivered notwithstanding that a substantial amount remainsunreleased in the delivery device. Loading an excess amount of drugfurther exacerbates the problems of dosage forms that are large anddifficult to swallow. Also, the added cost may be significant for activeagents having a high material or manufacturing cost. Consequently, thereis a need for improved delivery devices having an expandable push layerand a drug layer suitable for use with high drug loading that releasesubstantially all of the drug from the device to the environment of use.

SUMMARY OF THE INVENTION

[0012] In one aspect, the invention comprises a delivery device for anactive agent comprising a wall defining a cavity, the wall having anexit orifice formed or formable therein and at least a portion of thewall being semipermeable; an expandable layer located within the cavityremote from the exit orifice and in fluid communication with thesemipermeable portion of the wall; a drug layer located within thecavity adjacent the exit orifice and in direct or indirect contactingrelationship with the expandable layer; and a flow-promoting layerinterposed between the inner surface of the wall and at least theexternal surface of the drug layer located within the cavity.

[0013] In another aspect, the invention comprises an article ofmanufacture comprising a compressed drug composition overcoated with aflow-promoting layer. The compressed drug composition may be formed as alayer in direct or indirect contact with an expandable layer to form abilayer core that is overcoated with a flow-promoting layer.

[0014] In yet another aspect, the invention comprises a method offacilitating the release of a drug from a device comprising a compresseddrug composition, a semipermeable wall and a push-layer, the methodcomprising interposing a flow-promoting layer between the semi-permeablewall and the compressed drug composition.

BRIEF DESCRIPTION OF THE FIGURES

[0015]FIGS. 1A and 1B illustrate one embodiment of a dosage form of thisinvention, FIG. 1A illustrating the dosage form prior to administrationto a subject and FIG. 1B illustrating the dosage form at a period oftime after administration to a subject;

[0016]FIG. 2 illustrates a release profile (release rate as a functionof time) of the active agent nefazodone hydrochloride from arepresentative dosage form having the general characteristicsillustrated in FIG. 1, formed with an orifice of 190 mils and containing400 mg of nefazodone hydrochloride;

[0017]FIG. 3 illustrates a release profile (release rate as a functionof time) of the active agent nefazodone hydrochloride from arepresentative dosage form having the general characteristics of FIG. 1,formed with an orifice of 117 mils and containing 100 mg of nefazodonehydrochloride;

[0018]FIG. 4 illustrates the cumulative release of nefazodonehydrochloride over time for a number of representative dosage formscontaining polyethylene oxide-based nefazodone hydrochloridegranulations, with 100 mg loading of nefazodone hydrochloride and anorifice of 117 mils;

[0019]FIG. 5 illustrates the release profile (release rate as a functionof time) of the active agent nefazodone hydrochloride for representativedosage forms prepared in accordance with the procedure of Example 3;

[0020]FIG. 6 illustrates the cumulative release of nefazodonehydrochloride over time for representative dosage forms prepared inaccordance with the procedure of Example 3;

[0021]FIG. 7 illustrates the release profile (release rate as a functionof time) of the active agent nefazodone hydrochloride for representativedosage forms prepared in accordance with the procedure of Example 4;

[0022]FIG. 8 illustrates the cumulative release of nefazodonehydrochloride over time for representative dosage forms prepared inaccordance with the procedure of Example 4;

[0023]FIG. 9 illustrates the release profile (release rate as a functionof time) of the active agent nefazodone hydrochloride for representativedosage forms prepared in accordance with the procedure of Example 5;

[0024]FIG. 10 illustrates the cumulative release of nefazodonehydrochloride over time for representative dosage forms prepared inaccordance with the procedure of Example 5;

[0025] Figure 11 illustrates the release profile (release rate as afunction of time) of the active agent nefazodone hydrochloride forrepresentative dosage forms prepared in accordance with the procedure ofExample 6;

[0026]FIG. 12 illustrates the cumulative release of nefazodonehydrochloride over time for representative dosage forms prepared inaccordance with the procedure of Example 6; and

[0027] FIGS. 13A-13D provide a comparison of the release rate profileand cumulative release as a function of time for coated and uncoateddosage forms containing 400 mg of nefazodone hydrochloride.

DETAILED DESCRIPTION OF THE INVENTION

[0028] The present invention is best understood by reference to thefollowing definitions, the drawings and exemplary disclosure providedherein.

[0029] Definitions By “active agent”, “drug”, or “compound”, which areused interchangeably herein, is meant an agent, drug, compound,composition of matter or mixture thereof which provides somephysiological, psychological, biological, or pharmacological, and oftenbeneficial, effect when administered to a subject.

[0030] By “uniform rate of release” or “uniform release rate” is meant arate of release of the active agent from a dosage form that does notvary positively or negatively by more than 30% from the mean rate ofrelease of the active agent over a prolonged period of time, asdetermined in a USP Type 7 Interval Release Apparatus. Preferred uniformrates of release will vary by not more than 25% (positively ornegatively) from the mean rate of release determined over a prolongedperiod of time.

[0031] By “prolonged period of time” or “prolonged period” is meant acontinuous period of time of 4 hours or more, more typically 6 hours ormore.

[0032] By “dosage form” is meant a pharmaceutical composition or devicecomprising an active pharmaceutical agent, the composition or deviceoptionally containing inactive ingredients, such aspharmaceutically-acceptable carriers, excipients, suspension agents,surfactants, disintegrants, binders, diluents, lubricants, stabilizers,antioxidants, osmotic agents, colorants, plasticizers, and the like,that are used to manufacture and deliver active pharmaceutical agents.

[0033] By “pharmaceutically-acceptable acid addition salt” or“pharmaceutically-acceptable salt”, which are used interchangeablyherein, are meant those salts in which the anion does not contributesignificantly to the toxicity or pharmacological activity of the salt,and, as such, they are the pharmacological equivalents of the bases ofthe compounds to which they refer. Examples of pharmaceuticallyacceptable acids that are useful for the purposes of salt formationinclude but are not limited to hydrochloric, hydrobromic, hydroiodic,citric, acetic, benzoic, mandelic, phosphoric, nitric, mucic,isethionic, palmitic, and others.

[0034] By “sustained release ” is meant continuous release of activeagent to an environment over a prolonged period.

[0035] By “steady state” is meant the condition in which the amount ofdrug present in the blood plasma of a subject does not varysignificantly over a prolonged period of time.

[0036] By “C” is meant the concentration of drug in the blood plasma ofa subject, generally expressed as mass per unit volume, typicallynanograms per milliliter.

[0037] By “C_(max)” is meant the maximum concentration of drug in theblood plasma of a subject, generally expressed as mass per unit volume,typically nanograms per milliliter, within a specified time intervalafter administration of the drug to a subject.

[0038] By “C_(min)” is meant the minimum concentration of drug in theblood plasma of a subject, generally expressed as mass per unit volume,typically nanograms per milliliter, within a specified time intervalafter administration of the drug to a subject.

[0039] By “release rate assay” is meant a standardized assay for thedetermination of a compound using a USP Type 7 interval releaseapparatus substantially in accordance with the description of Example 2.It is understood that reagents of equivalent grade may be substituted inthe assay in accordance with generally-accepted procedures.

[0040] By “dry state” or “substantially dry state” is meant that thecomposition forming the drug layer of the dosage form is expelled fromthe dosage form in a plug-like state, the composition being sufficientlydry or so highly viscous that it does not readily flow as a liquidstream from the dosage form under the pressure exerted by the pushlayer.

[0041] One of the most suitable devices for the controlled release ofdrugs that require high loading in the dosage form to deliver an amountof drug having the desired therapeutic effect is that having asemipermeable wall defining a compartment, an expandable push layer anda drug layer in the compartment, and an exit orifice formed in thedosage form to permit the drug layer to be dispensed in a substantiallydry state to the environment of use. When manufacturing such dosageforms, a common practice is to fabricate a compressed tablet comprisingthe drug layer and the push layer. Typically, the push layercomposition, conveniently in granulated or powdered form, is compressedin a die cavity of a vertical tableting press. Then the drug layercomposition, also conveniently in granular or powdered form, is placedin the die cavity above the push layer and compressed as well to form abilayer tablet. Although the surface of the die cavity is quite smooth,the formed bilayer tablet may still be formed with surfaceirregularities. This is more of a problem with the drug layer,particularly when high drug loading is involved such that the amounts oflubricant, carrier and binder used may be limited due to sizeconstraints, than with the push layer.

[0042] In many applications the irregularities in the drug layer asdescribed above may be of little importance. However, when the druglayer is to be dispensed in a dry state from the compartment formed bythe semipermeable wall, the outer surface of the drug layer is pushedalong the inner surface of the semipermeable wall. Resistance tomovement of the drug layer will be present because of the frictionalforce existing between the two surfaces. The degree of resistance willincrease as the number and degree of irregularities in the externalsurface of the drug layer and the inner surface of the semipermeablewall increase. Furthermore, because it is practical to form thesemipermeable wall by coating the bilayer drug core, the inner surfaceof the semipermeable wall will initially conform to the irregularitiespresent in the external surface of the drug layer. Then when the druglayer is forced to move past the semipermeable wall, the irregularitieson the external surface of the drug layer must be forced over theirregularities on the inner surface of the semipermeable wall. Thiscreates friction and resistance to movement of the respective layers.While each of the surfaces is substantially a solid, it is convenient toview the relative movement of (i) the drug layer or drug layer/pushlayer composite and (ii) the semipermeable outer wall as a “flow” of thedrug layer from the device as the push layer expands. Thus, the innerlayer or subcoat is characterized as a “flow-promoting” layer. Ineffect, the flow-promoting layer is a layer of material interposedbetween the external surface of the drug layer and the internal surfaceof the semipermeable wall that reduces friction between the two andfacilitates the relative movement between them as fluid passes throughthe semipermeable wall and is imbibed by the expandable layer.

[0043] In systems without the flow promoting layer, the resistancebetween the drug layer and the outer semipermeable wall may createseveral problems. One is that the magnitude of the force resistingtransport of the drug layer may be a function of the relative positionsof the drug layer and the outer wall at any period in time. Variationsin the magnitude of the resisting force may cause variations in the rateat which the drug layer is expressed to the environment of use. Thiswould then cause variations in the release of drug from the dosage formand potentially variations in drug plasma levels of drug in the subjectover time. As can be seen from the release profiles of the dosage formsdescribed herein, with the practice of the invention active agent isuniformly released from the dosage forms over a prolonged period oftime. Such uniform release may provide significant pharmacologicaladvantages in the delivery of active agents.

[0044] Secondly, without the flow promoting layer being present, aportion of the drug layer tends to “stick” to the inner surface of theouter wall and remain in the dosage form as the rest of the drug layeris expressed to the environment of use by the expanding layer. Thisresidual amount of undispensed drug may be large; residual amounts ofmore than 20% to 30% of the initial drug layer loading have beenobserved under conditions of high drug loading.

[0045] The invention provides a dosage form, article of manufacture andmethod for the substantially complete release of a drug from the dosageform, particularly from dosage forms that may require high drug loadingin order to have the desired pharmacological effect. Dosage formsprepared in accordance with this invention may result in a depleteddosage form retaining 20% or less by weight, preferably 10% or less byweight, and most preferably 5% or less by weight of the initial amountof drug loaded in the dosage form when tested in a standard release rateassay.

[0046] High ranges of drug dosing, e.g. 100 to 2,000 mg of drug per unitdose, may require drug loading in the compositions to be administered of20% to 90% or more of the overall weight of the composition. Suchloading requirements may present problems in formulating compositionsand fabricating devices that are suitable for oral administration andcan be swallowed without undue difficulty. Loading requirements provideeven greater problems when formulating dosage forms that are to beadministered a limited number of times per day, such as for once-a-daydosing. Size problems are exacerbated when not all of the drugcomposition is released from the delivery device, since overloading ofthe drug, i.e. providing a quantity in the delivery device greater thanthat which will be released to the subject to provide the desiredpharmacological effect, is necessary to ensure that an appropriatequantity of drug is made available to the subject.

[0047] Dosage forms of this invention release effective amounts ofactive agent to the patient over a prolonged period of time and oftenprovide the opportunity for less frequent dosing, including once-a-daydosing, than previously required for immediate release compositions. Thedosage forms of this invention comprise a composition containing anactive agent, wherein the composition is externally coated with aflow-promoting layer.

[0048] Active agents include, inter allia, foods, food supplements,nutrients, drugs, antacids, vitamins, microorganism attenuators andother agents that benefit the environment of use. Active agents includeany physiologically or pharmacologically active substance that producesa localized or systemic effect or effects in animals, including warmblooded mammals, humans and primates; domestic household or farm animalssuch as cats, dogs, sheep, goats, cattle, horses and pigs; laboratoryanimals such as mice, rats and guinea pigs; zoo and wild animals; andthe like. Active agents that can be delivered include inorganic andorganic compounds, including, without limitation, active agents whichact on the peripheral nerves, adrenergic receptors, cholinergicreceptors, the skeletal muscles, the cardiovascular system, smoothmuscles, the blood circulatory system, synoptic sites, neuroeffectorjunctional sites, endocrine and hormone systems, the immunologicalsystem, the reproductive system, the skeletal system, autacoid systems,the alimentary and excretory systems, the histamine system and thecentral nervous system.

[0049] Suitable active agents may be selected from, for example,proteins, enzymes, enzyme inhibitors, hormones, polynucleotides,nucleoproteins, polysaccharides, glycoproteins, lipoproteins,polypeptides, steroids, hypnotics and sedatives, psychic energizers,tranquilizers, anticonvulsants, antidepressants, muscle relaxants,antiparkinson agents, analgesics, anti-inflammatories, antihystamines,local anesthetics, muscle contractants, antimicrobials, antimalarials,antivirals, antibiotics, antiobesity agents, hormonal agents includingcontraceptives, sympathomimetics, polypeptides and proteins capable ofeliciting physiological effects, diuretics, lipid regulating agents,antiandrogenic agents, antiparasitics, neoplastics, antineoplastics,antihyperglycemics, hypoglycemics, nutritional agents and supplements,growth supplements, fats, ophthalmics, antienteritis agents,electrolytes and diagnostic agents.

[0050] Examples of particular active agents useful in this inventioninclude prochlorperazine edisylate, ferrous sulfate, albuterol,aminocaproic acid, mecamylamine hydrochloride, procainamidehydrochloride, amphetamine sulfate, methamphetamine hydrochloride,benzphetamine hydrochloride, isoproterenol sulfate, phenmetrazinehydrochloride, bethanechol chloride, methacholine chloride, pilocarpinehydrochloride, atropine sulfate, scopolamine bromide, isopropamideiodide, tridihexethyl chloride, phenformin hydrochloride,methylphenidate hydrochloride, theophylline cholinate, cephalexinhydrochloride, diphenidol, meclizine hydrochloride, prochlorperazinemaleate, phenoxybenzamine, triethylperazine maleate, anisindione,diphenadione erythrityl tetranitrate, digoxin, isoflurophate,acetazolamide, nifedipine, methazolamide, bendroflumethiazide,chlorpropamide, glipizide, glyburide, gliclazide, tobutamide,chlorproamide, tolazamide, acetohexamide, metformin, troglitazone,orlistat, bupropion, nefazodone, tolazamide, chlormadinone acetate,phenaglycodol, allopurinol, aluminum aspirin, methotrexate, acetylsulfisoxazole, hydrocortisone, hydrocorticosterone acetate, cortisoneacetate, dexamethasone and its derivatives such as betamethasone,triamcinolone, methyltestosterone, 17-β-estradiol, ethinyl estradiol,ethinyl estradiol 3-methyl ether, prednisolone, 17-β-hydroxyprogesteroneacetate, 19-nor-progesterone, norgestrel, norethindrone, norethisterone,norethiederone, progesterone, norgesterone, norethynodrel, terfandine,fexofenadine, aspirin, acetaminophen, indomethacin, naproxen,fenoprofen, sulindac, indoprofen, nitroglycerin, isosorbide dinitrate,propranolol, timolol, atenolol, alprenolol, cimetidine, clonidine,imipramine, levodopa, selegiline, chlorpromazine, methyldopa,dihydroxyphenylalanine, calcium gluconate, ketoprofen, ibuprofen,cephalexin, erythromycin, haloperidol, zomepirac, ferrous lactate,vincamine, phenoxybenzamine, diltiazem, milrinone, captropril, mandol,quanbenz, hydrochlorothiazide, ranitidine, flurbiprofen, fenbufen,fluprofen, tolmetin, alclofenac, mefenamic, flufenamic, difuninal,nimodipine, nitrendipine, nisoldipine, nicardipine, felodipine,lidoflazine, tiapamil, gallopamil, amlodipine, mioflazine, lisinopril,enalapril, captopril, ramipril, enalaprilat, famotidine, nizatidine,sucralfate, etintidine, tetratolol, minoxidil, chlordiazepoxide,diazepam, amitriptyline, and imipramine, and pharmaceutical salts ofthese active agents. Further examples are proteins and peptides whichinclude, but are not limited to, insulin, colchicine, glucagon, thyroidstimulating hormone, parathyroid and pituitary hormones, calcitonin,renin, prolactin, corticotrophin, thyrotropic hormone, folliclestimulating hormone, chorionic gonadotropin, gonadotropin releasinghormone, bovine somatotropin, porcine somatropin, oxytocin, vasopressin,desmopressin, prolactin, somatostatin, lypressin, pancreozymin,luteinizing hormone, LHRH, interferons, interleukins, growth hormonessuch as human growth hormone, bovine growth hormone and porcine growthhormone, fertility inhibitors such as the prostaglandins, fertilitypromoters, growth factors, and human pancreas hormone releasing factor.

[0051] Active agents in the field of antidepressants may be selectedfrom the group consisting of tertiary amine tricyclics such as, forexample, amitriptyline, clomipramine, doxepin, imipramine,(+)-trimipramine; secondary amine tricyclics such as, for example,amozapine, desipramine, maprotiline, nortiriptyline, protryptilyline;serotonin re-uptake inhibitors such as, for example, fluoexetine,fluvoxamine, paroxetine, sertraline, venlafazine; and atypicalantidepressants such as brupropion, nefazodone, trazodone, phenelzine,tranylcypromirne, selegiline, and pharmaceutically acceptable saltsthereof. The dosage form typically may include a carrier, e.g.,hydrophilic polymer, in a composition with the active agent.

[0052] With reference to FIG. 1A, a preferred embodiment of a dosageform 1 of this invention having the “push-stick” configuration isillustrated prior to its administration to a subject. The dosage form 1comprises a wall 2 defining a cavity 3. Wall 2 is provided with an exitorifice 4. Within cavity 3 and remote from the exit orifice 4 is a pushlayer 5. A drug layer 6 is located within cavity 3 adjacent exit orifice4. In accordance with the invention, a flow-promoting layer 7, thefunction of which will be described and which may be formed as asecondary wall, extends between drug layer 6 and the inner surface ofwall 2.

[0053] The wall 2 is formed to be permeable to the passage of anexternal fluid, such as water and biological fluids, and it issubstantially impermeable to the passage of active agent, osmagent,osmopolymer and the like. As such, it is semipermeable. The selectivelysemipermeable compositions used for forming the wall are essentiallynonerodible and they are insoluble in biological fluids during the lifeof the dosage form. Wall 2 need not be semipermeable in its entirety.But at least a portion of wall 2 should be semipermeable to allow fluidto contact or communicate with push layer 5 such that push layer 5imbibes fluid during use. Specific materials for the fabrication ofsemipermeable wall 2 are well known in the art, and representativeexamples of such materials are described later herein.

[0054] Secondary wall 7, which functions as the flow-promoting layer, isin contacting position with the inner surface of the semipermeable wall2 and at least the external surface of the drug layer that is oppositewall 2; although the secondary wall 7 may, and preferably will, extendto, surround and contact the external surface of the push layer. Wall 7typically will surround at least that portion of the external surface ofthe drug layer that is opposite the internal surface of wall 2.Secondary wall 7 may be formed as a coating applied over the compressedcore comprising the drug layer and the push layer. The outersemipermeable wall 2 surrounds and encases the inner, secondary wall 7.Secondary wall 7 is preferably formed as a subcoat of at least thesurface of the drug layer 6, and optionally the entire external surfaceof the compacted drug layer 6 and the push layer 5. When thesemipermeable wall 2 is formed as a coat of the composite formed fromthe drug layer 6, the push layer 5 and the secondary wall 7, contact ofthe semipermeable wall 2 with the inner coat is assured.

[0055] Secondary wall 7 facilitates release of drug from the dosageforms of the invention. In dosage forms in which there is high drugloading, i.e., 20% or greater, but more generally 40% or greater, activeagent in the drug layer based on the overall weight of the drug layer,and no secondary wall, it has been observed that significant residualamounts of drug may remain in the device after the period of deliveryhas been completed. In some instances, residual drug amounts of greaterthat 20%, and even greater than 30%, by weight of the initial drugloading in the dosage form may remain in the dosage form at the end of atwenty-four hour period when tested in a release rate assay. Acomparison of the release of nefazodone hydrochloride from arepresentative dosage form of this invention having a flow promotinglayer and a dosage form not having the flow promoting layer (the detailsof which are provided in EXAMPLE 8) is shown in FIGS. 13A-13 D for adosage form having a drug loading of 83% (400 mg of nefazodonehydrochloride). FIGS. 13A and 13B are representative of the dosage formof the invention having a flow promoting layer and FIGS. 13C and 13D arerepresentative of a similar dosage form without the flow promotinglayer. The significant difference in the average, instantaneous releaserates and the cumulative release rates for the two dosage forms isapparent. Additionally, it is apparent that after 24 hours there issignificantly more drug remaining in the dosage form without the flowpromoting layer than drug remaining in the dosage form having the flowpromoting layer.

[0056] As noted above, the amount of residual drug may be advantageouslyreduced by the addition of secondary wall 7 formed as an inner coat of aflow-promoting agent, i.e., an agent that lowers the frictional forcebetween the outer, semi-permeable membrane wall 2 and the externalsurface of the drug layer 6. The secondary wall or inner coat 7 reducesthe frictional forces between the semipermeable wall 2 and the outersurface of the drug layer, thus allowing for more complete delivery ofdrug from the device. Particularly in the case of active compoundshaving a high cost, such an improvement presents substantial economicadvantages since it is not necessary to load the drug layer with anexcess of drug to insure that the minimal amount of drug required willbe delivered.

[0057] The inner subcoat 7 typically may be 0.01 to 5 mm thick, moretypically 0.5 to 5 mm thick, and it comprises a member selected fromhydrogels, gelatin, low molecular weight polyethylene oxides, e.g., lessthan 100,000 MW, hydroxyalkylcelluloses, e.g., hydroxyethylcellulose,hydroxypropylcellulose, hydroxyisopropylcelluose, hydroxybutylcelluloseand hydroxyphenylcellulose, and hydroxyalkyl alkylcelluloses, e.g.,hydroxypropyl methylcellulose, and mixtures thereof. Thehydroxyalkylcelluloses comprises polymers having a 9,500 to 1,250,000number-average molecular weight. For example, hydroxypropyl celluloseshaving number average molecular weights of between 80,000 to 850,000 areuseful. The flow promoting layer may be prepared from conventionalsolutions or suspensions of the aforementioned materials in aqueoussolvents or inert organic solvents. Preferred materials for the subcoator flow promoting layer include hydroxypropyl cellulose, hydroxyethylcellulose, hydroxypropyl methyl cellulose, povidone[poly(vinylpyrrolidone)], polyethylene glycol, and mixtures thereof.More preferred are mixtures of hydroxypropyl cellulose and povidone,prepared in organic solvents, particularly organic polar solvents suchas lower alkanols having 1-8 carbon atoms, preferably ethanol, mixturesof hydroxyethyl cellulose and hydroxypropyl methyl cellulose prepared inaqueous solution, and mixtures of hydroxyethyl cellulose andpolyethylene glycol prepared in aqueous solution. Most preferably, thesubcoat consists of a mixture of hydroxypropyl cellulose and povidoneprepared in ethanol. Conveniently, the weight of the subcoat applied tothe bilayer core may be correlated with the thickness of the subcoat andresidual drug remaining in a dosage form in a release rate assay such asdescribed herein. During manufacturing operations, the thickness of thesubcoat may be controlled by controlling the weight of the subcoat takenup in the coating operation. When the secondary wall 7 is formed as asubcoat, i.e., by coating onto the tableted bilayer composite drug layerand push layer, the subcoat can fill in surface irregularities formed onthe bilayer core by the tableting process. The resulting smooth externalsurface facilitates slippage between the coated bilayer composite andthe semipermeable wall during dispensing of the drug, resulting in alower amount of residual drug composition remaining in the device at theend of the dosing period. When wall 7 is fabricated of a gel-formingmaterial, contact with water in the environment of use facilitatesformation of a gel or gel-like inner coat having a viscosity that maypromote and enhance slippage between outer wall 2 and drug layer 6.

[0058] Representative polymers for forming wall 2 comprise semipermeablehomopolymers, semipermeable copolymers, and the like. Such materialscomprise cellulose esters, cellulose ethers and cellulose ester-ethers.The cellulosic polymers have a degree of substitution (DS) of theiranhydroglucose unit of from greater than 0 up to 3, inclusive. Degree ofsubstitution (DS) means the average number of hydroxyl groups originallypresent on the anhydroglucose unit that are replaced by a substitutinggroup or converted into another group. The anhydroglucose unit can bepartially or completely substituted with groups such as acyl, alkanoyl,alkenoyl, aroyl, alkyl, alkoxy, halogen, carboalkyl, alkylcarbamate,alkylcarbonate, alkylsulfonate, alkysulfamate, semipermeable polymerforming groups, and the like, wherein the organic moieties contain fromone to twelve carbon atoms, and preferably from one to eight carbonatoms.

[0059] The semipermeable compositions typically include a memberselected from the group consisting of cellulose acylate, cellulosediacylate, cellulose triacylate, cellulose acetate, cellulose diacetate,cellulose triacetate, mono-, di- and tri-cellulose alkanylates, mono-,di-, and tri-alkenylates, mono-, di-, and tri-aroylates, and the like.Exemplary polymers include cellulose acetate having a DS of 1.8 to 2.3and an acetyl content of 32 to 39.9%; cellulose diacetate having a DS of1 to 2 and an acetyl content of 21 to 35%; cellulose triacetate having aDS of 2 to 3 and an acetyl content of 34 to 44.8%; and the like. Morespecific cellulosic polymers include cellulose propionate having a DS of1.8 and a propionyl content of 38.5%; cellulose acetate propionatehaving an acetyl content of 1.5 to 7% and an acetyl content of 39 to42%; cellulose acetate propionate having an acetyl content of 2.5 to 3%,an average propionyl content of 39.2 to 45%, and a hydroxyl content of2.8 to 5.4%; cellulose acetate butyrate having a DS of 1.8, an acetylcontent of 13 to 15%, and a butyryl content of 34 to 39%; celluloseacetate butyrate having an acetyl content of 2 to 29%, a butyryl contentof 17 to 53%, and a hydroxyl content of 0.5 to 4.7%; cellulosetriacylates having a DS of 2.6 to 3, such as cellulose trivalerate,cellulose trilamate, cellulose tripalmitate, cellulose trioctanoate andcellulose tripropionate; cellulose diesters having a DS of 2.2 to 2.6,such as cellulose disuccinate, cellulose dipalmitate, cellulosedioctanoate, cellulose dicaprylate, and the like; and mixed celluloseesters, such as cellulose acetate valerate, cellulose acetate succinate,cellulose propionate succinate, cellulose acetate octanoate, cellulosevalerate palmitate, cellulose acetate heptanoate, and the like.Semipermeable polymers are known in U.S. Pat. No. 4,077,407, and theycan be synthesized by procedures described in Encyclopedia of PolymerScience and Technology, Vol. 3, pp. 325-354 (1964), IntersciencePublishers Inc., New York, N.Y.

[0060] Additional semipermeable polymers for forming the outer wall 2comprise cellulose acetaldehyde dimethyl acetate; cellulose acetateethylcarbamate; cellulose acetate methyl carbamate; cellulosedimethylaminoacetate; semipermeable polyamide; semipermeablepolyurethanes; semipermeable sulfonated polystyrenes; cross-linkedselectively semipermeable polymers formed by the coprecipitation of ananion and a cation, as disclosed in U.S. Pat. Nos. 3,173,876; 3,276,586;3,541,005; 3,541,006 and 3,546,142; semipermeable polymers, as disclosedby Loeb, et al. in U.S. Pat. No. 3,133,132; semipermeable polystyrenederivatives; semipermeable poly(sodium styrenesulfonate); semipermeablepoly(vinylbenzyltrimethylammonium chloride); and semipermeable polymersexhibiting a fluid permeability of 10⁻⁵ to 10⁻² (cc. mill/cm hr.atm),expressed as per atmosphere of hydrostatic or osmotic pressuredifferences across a semipermeable wall. The polymers are known to theart in U.S. Pat. Nos. 3,845,770; 3,916,899 and 4,160,020; and inHandbook of Common Polymers, Scott and Roff (1971) CRC Press, Cleveland,Ohio.

[0061] Wall 2 also can comprise a flux regulating agent. The fluxregulating agent is a compound added to assist in regulating the fluidpermeability or flux through wall 2. The flux regulating agent can be aflux enhancing agent or a decreasing agent. The agent can be preselectedto increase or decrease the liquid flux. Agents that produce a markedincrease in permeability to fluid such as water, are often essentiallyhydrophilic, while those that produce a marked decrease to fluids suchas water, are essentially hydrophobic. The amount of regulator in thewall when incorporated therein generally is from about 0.01% to 20% byweight or more. The flux regulator agents in one embodiment thatincrease flux include polyhydric alcohols, polyalkylene glycols,polyalkylenediols, polyesters of alkylene glycols, and the like. Typicalflux enhancers include polyethylene glycol 300, 400, 600, 1500, 4000,6000 and the like; low molecular weight gylcols such as polypropyleneglycol, polybutylene glycol and polyamylene glycol: thepolyalkylenediols such as poly(1,3-propanediol), poly(1,4-butanediol),poly(1,6-hexanediol), and the like; aliphatic diols such as 1,3-butyleneglycol, 1,4-pentamethylene glycol, 1,4-hexamethylene glycol, and thelike; alkylene triols such as glycerine, 1,2,3-butanetriol,1,2,4-hexanetriol, 1,3,6-hexanetriol and the like; esters such asethylene glycol dipropionate, ethylene glycol butyrate, butylene glycoldipropionate, glycerol acetate esters and the like. Representative fluxdecreasing agents include phthalates substituted with an alkyl or alkoxyor with both an alkyl and alkoxy group such as diethyl phthalate,dimethoxyethyl phthalate, dimethyl phthalate, and di(2-ethylhexyl)phthalate, aryl phthalates such as triphenyl phthalate, and butyl benzylphthalate; insoluble salts such as calcium sulphate, barium sulphate,calcium phosphate, and the like; insoluble oxides such as titaniumoxide; polymers in powder, granule and like form such as polystyrene,polymethylmethacrylate, polycarbonate, and polysulfone; esters such ascitric acid esters esterified with long chain alkyl groups; inert andsubstantially water impermeable fillers; resins compatible withcellulose based wall forming materials, and the like.

[0062] Other materials that can be used to form the wall 2 for impartingflexibility and elongation properties to the wall, for making wall 2less-to-nonbrittle and to render tear strength, include phthalateplasticizers such as dibenzyl phthalate, dihexyl phthalate, butyl octylphthalate, straight chain phthalates of six to eleven a carbons,di-isononyl phthalate, di-isodecyl phthalate, and the like. Theplasticizers include nonphthalates such as triacetin, dioctyl azelate,epoxidized tallate, tri-isoctyl trimellitate, tri-isononyl trimellitate,sucrose acetate isobutyrate, epoxidized soybean oil, and the like. Theamount of plasticizer in a wall when incorporated therein is about 0.01%to 20% weight, or higher.

[0063] The drug layer 6 comprises a composition formed of an activeagent and a carrier, such as a hydrophilic polymer. The hydrophilicpolymer provides a hydrophilic polymer particle in the drug compositionthat contributes to the uniform release rate of active agent andcontrolled delivery pattern. Representative examples of these polymersare poly(alkylene oxide) of 100,000 to 750,000 number-average molecularweight, including poly(ethylene oxide), poly(methylene oxide),poly(butylene oxide) and poly(hexylene oxide); and apoly(carboxymethylcellulose) of 40,000 to 400,000 number-averagemolecular weight, represented by poly(alkali carboxymethylcellulose),poly(sodium carboxymethylcellulose), poly(potassiumcarboxymethylcellulose) and poly(lithium carboxymethylcellulose). Thedrug composition can comprise a hydroxypropylalkylcellulose of 9,200 to125,000 number-average molecular weight for enhancing the deliveryproperties of the dosage form as represented byhydroxypropylethylcellulose, hydroxypropyl methylcellulose,hydroxypropylbutylcellulose and hydroxypropylpentylcellulose; and apoly(vinylpyrrolidone) of 7,000 to 75,000 number-average molecularweight for enhancing the flow properties of the dosage form. Preferredamong those polymers are the poly(ethylene oxide) of 100,000-300,000number average molecular weight. Carriers that erode in the gastricenvironment, i.e., bioerodible carriers, are especially preferred.

[0064] Surfactants and disintegrants may be utilized in the carrier aswell. Exemplary of the surfactants are those having an HLB value ofbetween about 10-25, such as polyethylene glycol 400 monostearate,polyoxyethylene-4-sorbitan monolaurate, polyoxyethylene-20-sorbitanmonooleate, polyoxyethylene-20-sorbitan monopalmitate,polyoxyethylene-20-monolaurate, polyoxyethylene-40 -stearate, sodiumoleate and the like. Disintegrants may be selected from starches, clays,celluloses, algins and gums and crosslinked starches, celluloses andpolymers. Representative disintegrants include corn starch, potatostarch, croscarmelose, crospovidone, sodium starch glycolate, Veegum HV,methylcellulose, agar, bentonite, carboxymethylcellulose, alginic acid,guar gum and the like.

[0065] The drug layer 6 is formed as a mixture containing an activeagent and the carrier. The drug layer may be formed from particles bycomminution that produces the size of the drug and the size of theaccompanying polymer used in the fabrication of the drug layer,typically as a core containing the compound, according to the mode andthe manner of the invention. The means for producing particles includegranulation, spray drying, sieving, lyophilization, crushing, grinding,jet milling, micronizing and chopping to produce the intended micronparticle size. The process can be performed by size reduction equipment,such as a micropulverizer mill, a fluid energy grinding mill, a grindingmill, a roller mill, a hammer mill, an attrition mill, a chaser mill, aball mill, a vibrating ball mill, an impact pulverizer mill, acentrifugal pulverizer, a coarse crusher and a fine crusher. The size ofthe particle can be ascertained by screening, including a grizzlyscreen, a flat screen, a vibrating screen, a revolving screen, a shakingscreen, an oscillating screen and a reciprocating screen. The processesand equipment for preparing drug and carrier particles are disclosed inPharmaceutical Sciences, Remington, 17th Ed., pp. 1585-1594 (1985);Chemical Engineers Handbook, Perry, 6th Ed., pp. 21-13 to 21-19 (1984);Journal of Pharmaceutical Sciences, Parrot, Vol. 61, No. 6, pp. 813-829(1974); and Chemical Engineer, Hixon, pp. 94-103 (1990).

[0066] The active compound may be provided in the drug layer in amountsof from 1 microgram to 5000 mg per dosage form, depending upon therequired dosing level that must be maintained over the delivery period,i.e., the time between consecutive administrations of the dosage forms.More typically, loading of compound in the dosage forms will providedoses of compound to the subject ranging from 1 microgram to 2500 mg perday, more usually 1 mg to 2500 mg per day. In many cases it may bepreferable to limit the amount of drug in each dosage form to less than1000 mg and meet daily dosing requirements greater than that amount byadministering more than one dosage form to a subject to meet the dailyrequirement. The drug layer typically will be a dry composition formedby compression of the carrier and the drug as one layer and theexpandable or push layer as the second layer. The expandable layer willpush the drug layer from the exit orifice as the push layer imbibesfluid from the environment of use, and the exposed drug layer will beeroded to release the drug into the environment of use. This may be seenwith reference to FIG. 1B.

[0067] The push layer 5 is an expandable layer having apush-displacement composition in direct or indirect contacting layeredarrangement with the drug layer 6. When in indirect contacting layeredarrangement, an inert element (not shown), such as a spacer layer ordisk, may be placed between the drug layer and the push layer.

[0068] Push layer 5 comprises a polymer that imbibes an aqueous orbiological fluid and swells to push the drug composition through theexit means of the device. Representatives of fluid-imbibing displacementpolymers comprise members selected from poly(alkylene oxide) of 1million to 15 million number-average molecular weight, as represented bypoly(ethylene oxide) and poly(alkali carboxymethylcellulose) of 500,000to 3,500,000 number-average molecular weight, wherein the alkali issodium, potassium or lithium. Examples of additional polymers for theformulation of the push-displacement composition comprise osmopolymerscomprising polymers that form hydrogels, such as Carbopol® acidiccarboxypolymer, a polymer of acrylic cross-linked with a polyallylsucrose, also known as carboxypolymethylene, and carboxyvinyl polymerhaving a molecular weight of 250,000 to 4,000,000; Cyanamer®polyacrylamides; cross-linked water swellable indenemaleic anhydridepolymers; Good-rite® polyacrylic acid having a molecular weight of80,000 to 200,000; Aqua-Keeps® acrylate polymer polysaccharides composedof condensed glucose units, such as diester cross-linked polygluran; andthe like. Representative polymers that form hydrogels are known to theprior art in U.S. Pat. No. 3,865,108, issued to Hartop; U.S. Pat. No.4,002,173, issued to Manning; U.S. Pat. No. 4,207,893, issued toMichaels; and in Handbook of Common Polymers, Scott and Roff, ChemicalRubber Co., Cleveland, Ohio.

[0069] The osmagent, also known as osmotic solute and osmoticallyeffective agent, which exhibits an osmotic pressure gradient across theouter wall and subcoat, comprises a member selected from the groupconsisting of sodium chloride, potassium chloride, lithium chloride,magnesium sulfate, magnesium chloride, potassium sulfate, sodiumsulfate, lithium sulfate, potassium acid phosphate, mannitol, urea,inositol, magnesium succinate, tartaric acid raffinose, sucrose,glucose, lactose, sorbitol, inorganic salts, organic salts andcarbohydrates.

[0070] Exemplary solvents suitable for manufacturing the respectivewalls, layers, coatings and subcoatings utilized in the dosage forms ofthe invention comprise aqueous and inert organic solvents that do notadversely harm the materials utilized to fabricate the dosage forms. Thesolvents broadly include members selected from the group consisting ofaqueous solvents, alcohols, ketones, esters, ethers, aliphatichydrocarbons, halogenated solvents, cycloaliphatics, aromatics,heterocyclic solvents and mixtures thereof. Typical solvents includeacetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butylalcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butylacetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane,n-heptane, ethylene glycol monoethyl ether, ethylene glycol monoethylacetate, methylene dichloride, ethylene dichloride, propylenedichloride, carbon tetrachloride nitroethane, nitropropanetetrachloroethane, ethyl ether, isopropyl ether, cyclohexane,cyclooctane, benzene, toluene, naphtha, 1,4-dioxane, tetrahydrofuran,diglyme, water, aqueous solvents containing inorganic salts such assodium chloride, calcium chloride, and the like, and mixtures thereofsuch as acetone and water, acetone and methanol, acetone and ethylalcohol, methylene dichloride and methanol, and ethylene dichloride andmethanol.

[0071] Pan coating may be conveniently used to provide the completeddosage form, except for the exit orifice. In the pan coating system, thesubcoat of the wall-forming compositions is deposited by successivespraying of the respective composition on the bilayered core comprisingthe drug layer and the push layer accompanied by tumbling in a rotatingpan. A pan coater is used because of its availability at commercialscale. Other techniques can be used for coating the drug core. Thecoated dosage form may be dried in a forced-air oven, or in atemperature and humidity controlled oven to free the dosage form ofsolvent. Drying conditions will be conventionally chosen on the basis ofavailable equipment, ambient conditions, solvents, coatings, coatingthickness, and the like.

[0072] Other coating techniques can also be employed. For example, thesemipermeable wall and the subcoat of the dosage form can be formed inone technique using the air-suspension procedure. This procedureconsists of suspending and tumbling the bilayer core in a current ofair, an inner subcoat composition and an outer semipermeable wallforming composition, until, in either operation, the subcoat and theouter wall coat is applied to the bilayer core. The air-suspensionprocedure is well suited for independently forming the wall of thedosage form. The air-suspension procedure is described in U.S. Pat. No.2,799,241; in J. Am. Pharm. Assoc., Vol. 48, pp. 451-459 (1959); and,ibid., Vol. 49, pp. 82-84 (1960). The dosage form also can be coatedwith a Wurster® air-suspension coater using, for example, methylenedichloride methanol as a cosolvent. An Aeromatic® air-suspension coatercan be used employing a cosolvent.

[0073] The dosage form of the invention may be manufactured by standardtechniques. For example, the dosage form may be manufactured by the wetgranulation technique. In the wet granulation technique, the drug andthe ingredients comprising the first layer or drug composition areblended using an organic solvent, such as denatured anhydrous ethanol,as the granulation fluid. The ingredients forming the first layer ordrug composition are individually passed through a preselected screenand then thoroughly blended in a mixer. Next, other ingredientscomprising the first layer can be dissolved in a portion of thegranulation fluid, such as the solvent described above. Then, the latterprepared wet blend is slowly added to the drug blend with continualmixing in the blender. The granulating fluid is added until a wet blendis produced, which wet mass blend is then forced through a predeterminedscreen onto oven trays. The blend is dried for 18 to 24 hours at 24° C.to 35° C. in a forced-air oven. The dried granules are then sized. Next,magnesium stearate is added to the drug granulation, then put intomilling jars and mixed on a jar mill for 10 minutes. The composition ispressed into a layer, for example, in a Manesty® press. The speed of thepress is set at 20 rpm and the maximum load set at 2 tons. The firstlayer is pressed against the composition forming the second layer andthe bilayer tablets are fed to the Kilian® Dry Coater press andsurrounded with the drug-free coat, followed by the exterior wallsolvent coating.

[0074] In another manufacture the beneficial drug and other ingredientscomprising the first layer facing the exit means are blended and pressedinto a solid layer. The layer possesses dimensions that correspond tothe internal dimensions of the area the layer is to occupy in the dosageform, and it also possesses dimensions corresponding to the second layerfor forming a contacting arrangement therewith. The drug and otheringredients can also be blended with a solvent and mixed into a solid orsemisolid form by conventional methods, such as ballmilling,calendering, stirring or rollmilling, and then pressed into apreselected shape. Next, the expandable layer, e.g., a layer ofosmopolymer composition, is placed in contact with the layer of drug ina like manner. The layering of the drug formulation and the osmopolymerlayer can be fabricated by conventional two-layer press techniques. Thetwo contacted layers are first coated with the flow-promoting subcoatand then an outer semipermeable wall. The air-suspension andair-tumbling procedures comprise in suspending and tumbling the pressed,contacting first and second layers in a current of air containing thedelayed-forming composition until the first and second layers aresurrounded by the wall composition.

[0075] Another manufacturing process that can be used for providing thecompartment-forming composition comprises blending the powderedingredients in a fluid bed granulator. After the powdered ingredientsare dry blended in the granulator, a granulating fluid, for example,poly(vinylpyrrolidone) in water, is sprayed onto the powders. The coatedpowders are then dried in the granulator. This process granulates allthe ingredients present therein while adding the granulating fluid.After the granules are dried, a lubricant, such as stearic acid ormagnesium stearate, is mixed into the granulation using a tote orV-blender. The granules are then pressed in the manner described above.

[0076] The dosage form of the invention is provided with at least oneexit orifice. The exit orifice cooperates with the drug core for theuniform release of drug from the dosage form. The exit orifice can beprovided during the manufacture of the dosage form or during drugdelivery by the dosage form in a fluid environment of use. Theexpression “exit orifice” as used for the purpose of this inventionincludes a member selected from the group consisting of a passageway; anaperture; an orifice; and a bore. The expression also includes anorifice that is formed from a substance or polymer that erodes,dissolves or is leached from the outer coat or wall or inner coat toform an exit orifice. The substance or polymer may include an erodiblepoly(glycolic) acid or poly(lactic) acid in the outer or inner coats; agelatinous filament; a water-removable poly(vinyl alcohol); a leachablecompound, such as a fluid removable pore-former selected from the groupconsisting of inorganic and organic salt, oxide and carbohydrate. Anexit, or a plurality of exits, can be formed by leaching a memberselected from the group consisting of sorbitol, lactose, fructose,glucose, mannose, galactose, talose, sodium chloride, potassiumchloride, sodium citrate and mannitol to provide a uniform-releasedimensioned pore-exit orifice. The exit orifice can have any shape, suchas round, triangular, square, elliptical and the like for the uniformmetered dose release of a drug from the dosage form. The dosage form canbe constructed with one or more exits in spaced apart relation or one ormore surfaces of the dosage form. The exit orifice can be performed bydrilling, including mechanical and laser drilling, through the outercoat, the inner coat, or both. Exits and equipment for forming exits aredisclosed in U.S. Pat. Nos. 3,845,770 and 3,916,899, by Theeuwes andHiguchi; in U.S. Pat. No. 4,063,064, by Saunders, et al.; and in U.S.Pat. No. 4,088,864, by Theeuwes, et al. The exit orifice may be from 10%to 100% of the inner diameter of the compartment formed by wall 2,preferably from 30% to 100%, and most preferably from 50% to 100%.

[0077] Notwithstanding that some of the dosage forms of the inventionmay require high drug loading to elicit a desired patient response,dosage forms of the present invention which provide a uniform releaserate of the active compound may allow one to use a lesser amount ofcompound per dosage form per day than would be calculated from simplymultiplying the dose of active agent in the immediate release product bythe number of times it is recommended to administer the immediaterelease product in a day.

[0078] Even at high dosage levels in which the active compound ispresent from 40% to 90% by weight of the drug layer composition, theinstant dosage forms and devices are able to effectively release therequired amount of active compound over a prolonged period of time at auniform release rate. Preferably, the weight percent of active compoundin the dosage forms of the invention will be 75% or less, and mostpreferably less than 70%, but 40% or greater, most preferably greaterthan 60%, based on the weight of drug layer composition, to allow fordosage forms that may be easily swallowed. In circumstances where it isdesirable to administer an amount of drug that would exceed 75% of thedrug layer composition, it is usually preferred to simultaneouslyadminister two tablets or more of the dosage form with a total drugloading equal to the greater amount that would have been used in thesingle tablet.

[0079] The invention may be illustrated with once-a-day dosage formsprepared with 100 mg, 200 mg, 300 mg, 400 mg and 500 mg of nefazodonehydrochloride per dosage form. In each case, less than 10% of theinitial quantity of drug remained in the dosage form after 24 hours whentested in the release rate assay. After an initial start-up period,usually approximately 2-3 hours or less, the dosage forms provide auniform rate of release of compound over a prolonged period of time,typically 4 hours to 20 hours or more, often for 4 hours to 16 hours,and more usually for a time period of 4 hours to 10 hours. At the end ofa prolonged period of uniform release, the rate of release of drug fromthe dosage form may decline somewhat over a period of time, such asseveral hours. The dosage forms provide therapeutically effectiveamounts of drug for a broad range of applications and individual subjectneeds.

[0080] Upon initial administration, the dosage forms may provide a drugconcentration in the plasma of the subject that increases over aninitial period of time, typically several hours or less, and thenprovide a relatively constant concentration of drug in the plasma over aprolonged period of time, typically 4 hours to 24 hours or more. Therelease profiles of the dosage forms of this invention provide releaseof drug over the entire 24-hour period corresponding to once-a-dayadministration, such that steady state concentration of drug in bloodplasma of a subject may be maintained at therapeutically effectivelevels over a 24 hour period after administration the sustained releasedosage form. Steady state plasma levels of drug may typically beachieved after twenty-four hours or, in some cases, several days, e.g.,2-5 days, in most subjects.

[0081] For systems having 100 mg, 200 mg, 300 mg, 400 mg and 500 mg ofnefazodone hydrochloride, manufactured substantially in accordance withthe procedures described in Example 1 and having a T₉₀ of 12 hours, forexample, nefazodone hydrochloride is released at average release ratesof 8.6, 17.2, 25.8, 34.4 and 43.0 mg per hour, respectively, over acontinuous period of time of 4 hours or more, generally for a continuousperiod of about 4 to 10 hours, as determined in the release rate assay,beginning approximately 2-3 hours after initial exposure to the bath. Ineach of those formulations, the percentage of drug loading based on theoverall weight of the drug layer is about 69% for the 100 mg, 200 mg,300 mg, 400 mg and 500 mg dosage forms. In each instance nefazodonehydrochloride was released from the dosage form at a uniform releaserate over a prolonged period of time.

[0082] Release rate as a function of time for a representative dosageform containing 400 mg of nefazodone hydrochloride is illustrated inFIG. 2. The dosage form had a T₉₀ equal to 17.7 hours and a mean releaserate of about 22 mg/hr. The dosage form was fabricated with an exitorifice of 190 mils, a 40 mg subcoat formed of 70/30 wt %Klucel/PVPK29-32 and a semipermeable membrane coat weighing 70.4 mg of90/10 wt % cellulose acetate 398 and polyethylene glycol 3350. In FIG. 3the release rates for a similarly fabricated dosage form having a T₉₀ of18.5 hours and a mean release rate of about 5.2 mg/hr is illustrated.The dosage form is fabricated with an exit orifice of 117 mils, a 10.6mg subcoat formed of 70/30 wt % Klucel/PVPK29-32 and a semipermeablemembrane coat weighing 46.9 mg of 97/3 wt % cellulose acetate 398 andpolyethylene glycol 3350. In each case, the drug layer contained 65%nefazodone hydrochloride. As can be seen from those figures, theprolonged period of uniform rate of release extends from approximately 4hours to about 18 hours for the dosage form of FIG. 2 and from about 2hours to about 16 hours for the dosage form of FIG. 3.

[0083] With respect to the 100-400 mg dosage forms prepared as describedherein, it has been found that, for a 100 mg dosage form having a corediameter of about {fraction (3/16)} inch, an exit orifice of 110-130mils, preferably 115-125 mils, and most preferably 120 mils, provides aneffective release profile. For a 200 mg dosage form having a corediameter of about {fraction (15/64)} inch, an exit orifice of 145-165mils, preferably 150-160 mils, and most preferably 155 mils, provides aneffective release profile. For a 300 mg dosage form having a corediameter of about {fraction (17/64)} inch, an exit orifice of 165-185mils, preferably 170-180 mils, and most preferably 175 mils, provides aneffective release profile. For a 400 mg dosage form having a corediameter of about {fraction (9/32)} inch, an exit orifice of 180-200mils, preferably 185-195 mils, and most preferably 190 mils, provides aneffective release profile. The dosage forms release drug at a rate thatvaries less than 30% from the mean rate of release measured over aprolonged period of time. Preferably, the devices release drug at a ratethat varies less than 25% from the mean rate of release measured over aprolonged period of time.

[0084] Dosage forms of this invention release drug at a uniform rate ofrelease over a prolonged period of time as determined in a standardrelease rate assay such as that described herein. When administered to asubject, the dosage forms of the invention provide blood plasma levelsof drug in the subject that are less variable over a prolonged period oftime than those obtained with immediate release dosage forms. When thedosage forms of this invention are administered on a regular, once-a-daybasis, the dosage forms of the invention provide steady state plasmalevels of drug such that the difference between C_(max) and C_(min) overthe 24-hour period is substantially reduced over that obtained fromadministration of an immediate release product that is intended torelease the same amount of drug in the 24-hour period as is providedfrom the dosage forms of the invention

[0085] The dosage forms of this invention are adapted to release activeagent at a uniform rate of release rate over a prolonged period of time,preferably 6 hours or more. Measurements of release rate are typicallymade in vitro, in acidified water to provide a simulation of conditionsin gastric fluid, and are made over finite, incremental time periods toprovide an approximation of instantaneous release rate. Information ofsuch in vitro release rates with respect to a particular dosage form maybe used to assist in selection of dosage form that will provide desiredin vivo results. Such results may be determined by present methods, suchas blood plasma assays and clinical observation, utilized bypractitioners for prescribing available immediate release dosage forms.

[0086] It has been found that dosage forms of the present inventionhaving release rate profiles as defined herein may provide to a patienta substantially constant blood plasma concentration and a sustainedtherapeutic effect of active agent, after administration of the dosageform, over a prolonged period of time. The sustained release dosageforms of this invention demonstrate less variability in drug plasmaconcentration over a 24-hour period than do immediate releaseformulations, which characteristically create significant peaks in drugconcentration shortly or soon after administration to the subject.

[0087] The practice of the foregoing method by orally administering adosage form of the invention to a subject once-a-day for the treatmentof disease states or symptoms responsive to the active agent of thedosage form is preferred.

[0088] A preferred method of manufacturing dosage forms in accordancewith the present invention is generally described below. Percentages arepercentages by weight unless noted otherwise.

EXAMPLE 1

[0089] Preparation of the Drug Layer Granulation

[0090] A binder solution is prepared by adding hydroxypropyl cellulose(Klucel MF, Aqualon Company), “HPC”, to water to form a solutioncontaining 5 mg of HPC per 0.995 grams of water. The solution is mixeduntil the hydroxypropyl cellulose is dissolved. For a particular batchsize, a fluid bed granulator (“FBG”) bowl is charged with the requiredamounts of nefazodone HCI (69.0%), polyethylene oxide (MW 200,000)(Polyox® N-80, Union Carbide Corporation) (20.3%), hydroxypropylcellulose (Klucel MF) (5%), polyoxyl 40 stearate (3%) and crospovidone(2%). After mixing the dry materials in the bowl, the binder solutionprepared as above is added. Then the granulation is dried in the FBG toa consistency suitable for milling (<1% by weight water), and thegranulation is milled through a 7 or a 10 mesh screen.

[0091] The granulation is transferred to a tote blender or a V-blender.The required amounts of antioxidant, butylated hydroxytoluene (“BHT”)(0.01%), and lubricant, stearic acid (1%), are sized through a 40 meshscreen and both are blended into the granulation using the tote orV-blender until uniformly dispersed (about 1 minute of blending forstearic acid and about 10 minutes of blending for BHT.

[0092] Preparation of the Osmotic Push Layer Granulation

[0093] A binder solution is prepared by adding hydroxypropylmethylcellulose 2910 (“HPMC”) to water in a ratio of 5 mg of HPMC to 1 gof water. The solution is mixed until the HPMC is dissolved. Sodiumchloride powder (30%) and red ferric oxide (1.0%) are milled andscreened. A fluid bed granulator (“FBG”) bowl is charged with therequired amounts of polyethylene oxide (MW 7,000,000) (Polyox® 303)(63.7%), HPMC (5.0%), the sodium chloride and the red ferric oxide.After mixing the dry materials in the bowl, the binder solution preparedabove is added. The granulation is dried in the FBG until the targetmoisture content (<1% by weight water) is reached. The granulation ismilled through a 7 mesh screen and transferred to a tote blender or aV-blender. The required amount of antioxidant, butylated hydroxytoluene(0.08%), is sized through a 60 mesh screen. The required amount oflubricant, stearic acid (0.25%), is sized through a 40 mesh screen andboth materials are blended into the granulation using the tote orV-blender until uniformly dispersed (about 1 minute for stearic acid andabout 10 minutes for BHT).

[0094] Bilayer Core Compression

[0095] A longitudinal tablet press (Korsch press) is set up with round,deep concave punches and dies. Two feed hoppers are placed on the press.The drug layer prepared as above is placed in one of the hoppers whilethe osmotic push layer prepared as above is placed in the remaininghopper.

[0096] The initial adjustment of the tableting parameters (drug layer)is performed to produce cores with a uniform target drug layer weight,typically 100 mg of drug in each tablet. The second layer adjustment(osmotic push layer) of the tableting parameters is performed whichbonds the drug layer to the osmotic layer to produce cores with auniform final core weight, thickness, hardness, and friability. Theforegoing parameters can be adjusted by varying the fill space and/orthe force setting. A typical tablet containing a target amount of 100 mgof drug will be approximately 0.465 inches long and approximately 0.188inches in diameter.

[0097] Preparation of the Subcoat Solution and Subcoated System

[0098] The subcoat solution is prepared in a covered stainless steelvessel. The appropriate amounts of povidone (K29-32) (2.4%) andhydroxypropyl cellulose (MW 80,000) (Klucel EF, Aqualon Company) (5.6%)are mixed into anhydrous ethyl alcohol (92%) until the resultingsolution is clear. The bilayer cores prepared above are placed into arotating, perforated pan coating unit. The coater is started and afterthe coating temperature of 28-36° C. is attained, the subcoatingsolution prepared above is uniformly applied to the rotating tablet bed.When a sufficient amount of solution has been applied to provide thedesired subcoat weight gain, the subcoat process is stopped. The desiredsubcoat weight will be selected to provide acceptable residuals of drugremaining in the dosage form as determined in the release rate assay fora 24-hour period. Generally, it is desirable to have less than 10%, morepreferably less than 5%, and most preferably less than 3% of residualdrug remaining after 24 hours of testing in a standard release rateassay as described herein, based on the initial drug loading. This maybe determined from the correlation between subcoat weight and theresidual drug for a number of dosage forms having the same bilayer corebut different subcoat weights in the standard release rate assay.

[0099] Preparation of the Rate Controlling Membrane and Membrane CoatedSystem

[0100] Subcoated bilayer cores prepared as above are placed into arotating, perforated pan coating unit. The coater is started, and afterthe coating temperature (28-38° C.) is attained, the appropriate coatingsolution prepared as in A, B or C below is uniformly applied to therotating tablet bed until the desired membrane wt gain is obtained. Atregular intervals throughout the coating process, the weight gain isdetermined and sample membrane coated units may be tested in the releaserate assay to determine a T₉₀ for the coated units. Weight gain may becorrelated with T₉₀ for membranes of varying thickness in the releaserate assay. When sufficient amount of solution has been applied,conveniently determined by attainment of the desired membrane weightgain for a desired T₉₀, the membrane coating process is stopped.

[0101] A. A coating solution is prepared in a covered stainless steelvessel. The appropriate amounts of acetone (565 mg) and water (29.7 mg)are mixed with the poloxamer 188 (1.6 mg) and cellulose acetate (29.7mg) until the solids are completely dissolved. The coating solution hasabout 5% solids upon application. The membrane yields a dosage formhaving a T₉₀ of about 13 hours in the release rate assay.

[0102] B. Acetone (505.4 mg) is mixed with cellulose acetate (27.72 mg)until the cellulose acetate is completely dissolved. Polyethylene glycol3350 (0.28 mg) and water (26.6 mg) are mixed in separate container. Thetwo solutions are mixed together until the resulting solution is clear.The coating solution has about 5% solids upon application. The membraneyields a dosage form having a T₉₀ of about 13 hours (i.e., approximately90% of the drug is released from the dosage form in 13 hours), asdetermined in the release rate assay.

[0103] C. Acetone (776.2 mg) is mixed with cellulose acetate (42.57 mg)until the cellulose acetate is completely dissolved. Polyethylene glycol3350 (0.43 mg) and water (40.9 mg) are mixed in separate container. Thetwo solutions are mixed together until the resulting solution is clear.The coating solution has about 5% solids upon application. The membraneyields a dosage form having a T₉₀ of about 18 hours (i.e., approximately90% of the drug is released from the dosage form in 18 hours), asdetermined in the release rate assay.

[0104] Drilling of Membrane Coated Systems

[0105] One exit port is drilled into the drug layer end of the membranecoated system. During the drilling process, samples are checked atregular intervals for orifice size, location, and number of exit ports.

[0106] Drying of Drilled Coated Systems

[0107] Drilled coated systems prepared as above are placed on perforatedoven trays which are placed on a rack in a relative humidity oven(43-45% relative humidity) and dried to remove the remaining solvents.

[0108] Color and Clear Overcoats

[0109] Optional color or clear coats solutions are prepared in a coveredstainless steel vessel. For the color coat 88 parts of purified water ismixed with 12 parts of Opadry II [color not critical] until the solutionis homogeneous. For the clear coat 90 parts of purified water is mixedwith 10 parts of Opadry Clear until the solution is homogeneous. Thedried cores prepared as above are placed into a rotating, perforated pancoating unit. The coater is started and after the coating temperature isattained (35-45° C.), the color coat solution is uniformly applied tothe rotating tablet bed. When sufficient amount of solution has beenapplied, as conveniently determined when the desired color overcoatweight gain has been achieved, the color coat process is stopped. Next,the clear coat solution is uniformly applied to the rotating tablet bed.When sufficient amount of solution has been applied, or the desiredclear coat weight gain has been achieved, the clear coat process isstopped. A flow agent (e.g., Car-nu-bo wax) is applied to the tablet bedafter clear coat application.

EXAMPLE 2

[0110] The release rate of drug from devices containing the dosage formsof the invention is determined in the following standardized assay. Themethod involves releasing systems into acidified water (pH 3). Aliquotsof sample release rate solutions are injected onto a chromatographicsystem to quantify the amount of drug released during specified testintervals. Drug is resolved on a C₁₈ column and detected by UVabsorption (254 nm for nefazodone hydrochloride). Quatitation isperformed by linear regression analysis of peak areas from a standardcurve containing at least five standard points.

[0111] Samples are prepared with the use of a USP Type 7 IntervalRelease Apparatus. Each system (invention device) to be tested isweighed. Then, each system is glued to a plastic rod having a sharpenedend, and each rod is attached to a release rate dipper arm. Each releaserate dipper arm is affixed to an up/down reciprocating shaker (USP Type7 Interval Release Apparatus), operating at an amplitude of about 3 cmand 2 to 4 seconds per cycle. The rod ends with the attached systems arecontinually immersed in 50 ml calibrated test tubes containing 50 ml ofacidified H₂O (acidified to pH 3.00±0.05 with phosphoric acid),equilibrated in a constant temperature water bath controlled at 37°C.±0.5° C. At the end of each time interval specified, typically onehour or two hours, the systems are transferred to the next row of testtubes containing fresh acidified water. The process is repeated for thedesired number of intervals until release is complete. Then the solutiontubes containing released drug are removed and allowed to cool to roomtemperature. After cooling, each tube is filled to the 50 ml mark withacidified water, each of the solutions is mixed thoroughly, and thentransferred to sample vials for analysis by high pressure liquidchromatography (“HPLC”). Standard solutions of drug are prepared inconcentration increments encompassing the range of 5 micrograms to about400 micrograms and analyzed by HPLC. A standard concentration curve isconstructed using linear regression analysis. Samples of drug obtainedfrom the release test are analyzed by HPLC and concentration of drug isdetermined by linear regression analysis. The amount of drug released ineach release interval is calculated. The results for various dosageforms of the invention are 16 illustrated in FIGS. 2-13.

EXAMPLE 3

[0112] Employing the general procedure of EXAMPLE 1 and proportionateamounts of materials (all percentages expressed as weight percentages),the following dosage form containing 100 mg nefazodone hydrochloride isprepared.

[0113] A drug layer having a weight of 145.0 mg consisting of 69%nefazodone hydrochloride, 20.24% polyethylene oxide (Polyox N-80), 5%hydroxypropyl cellulose (Klucel MF), 3% polyoxyl 40 stearate (MYRJ 52S),2% crospovidone (PVP XL), 0.75% stearic acid and 0.01% butylatedhydroxytoluene (BHT) is prepared. A push layer is prepared having aweight of 92 mg consisting of 63.67% polyethylene oxide (Polyox 303),30.0% sodium chloride, 5% hydroxypropyl methylcellulose (HPMC E-5), 1%red ferric oxide, 0.25% stearic acid and 0.08% BHT. The bilayer corecomprising the drug layer and the push layer is tableted as described.

[0114] Next, a subcoat is prepared with 70% Klucel EF and 30% povidoneK29-32 with ethanol as the solvent. The subcoat contains 8% solids onapplication. After application, the amount of the subcoat on the bilayercore is 13.5 mg. The semi-permeable membrane is prepared with 99%cellulose acetate 398-10 and 1% polyethylene glycol 3350 with a solventsystem of 95% acetone and 5% water. The membrane coat contains 5% solidson application, and the weight of the membrane on the subcoated bilayercore after application is 43.8 mg.

[0115] An orifice having a diameter of 114 mils is drilled in the dosageforms, which are then dried at 45° C. and 45% relative humidity forabout 120 hours and dried for an additional 5 hours at 45° C. atotherwise ambient conditions.

[0116] The dosage forms are assayed for release of nefazodonehydrochloride in the assay described in Example 2. The release rates fortwelve individual dosage forms and the cumulative percent of dosereleased are represented in FIG. 5 and FIG. 6, respectively. The dosageforms exhibit a nominal T₉₀ of 18.3 hours and a mean release rate of 5.2mg/hr over a prolonged period of time, extending substantially frominterval 4 to interval 18. It is observed that the dosage forms releasenefazodone hydrochloride at a uniform rate of release over a prolongedperiod of time.

[0117] When the weight of cellulose acetate in the semi-permeablemembrane is reduced to 28.5 mg, 1.5 mg of poloxamer 188 is substitutedfor the polyethylene glycol plasticizer, and the semi-permeable membraneis applied to achieve a per dosage weight of about 26 mg, a dosage formhaving a T₉₀ of about 12 hours is produced.

[0118] When the weight of cellulose acetate in the semi-permeablemembrane is reduced to 27.2 mg and the amount of polyethylene glycolplasticizer is reduced to 0.28 mg, and the semi-permeable membrane isapplied to achieve a per dosage weight of about 28 mg, a dosage formhaving a T₉₀ of about 13 hours is produced.

EXAMPLE 4

[0119] Employing the general procedure of EXAMPLE 1 and proportionateamounts of materials (all percentages expressed as weight percentages),the following dosage form containing 200 mg nefazodone hydrochloride isprepared:

[0120] A drug layer having a weight of 290 mg consisting of 69%nefazodone hydrochloride, 20.24% polyethylene oxide (Polyox N-80), 5%hydroxypropyl cellulose (Klucel MF), 3% polyoxyl 40 stearate (MYRJ 52S),2% crospovidone (PVP XL), 0.75% stearic acid and 0.01% butylatedhydroxytoluene (BHT) is prepared. A push layer is prepared having aweight 145 mg consisting of 64.10% polyethylene oxide (Polyox 303),30.0% sodium chloride, 5% hydroxypropyl methylcellulose (HPMC E-5), 0.5%red ferric oxide, 0.25% stearic acid and 0.08% BHT. The bilayer corecomprising the drug layer and the push layer is tableted as described.

[0121] Next, a subcoat is prepared with 70% Klucel EF and 30% povidoneK29-32 with ethanol as the solvent. After application, the amount of thesubcoat on the bilayer core is 23.6 mg. The semi-permeable membrane isprepared with 90% cellulose acetate 398-10 and 10% polyoxamer (PluronicsF68, BASF Corporation) with a solvent system of 95% acetone and 5%water. The weight of the membrane coat on the subcoated bilayer coreafter application is 37.5 mg.

[0122] An orifice having a diameter of 155 mils is drilled in the dosageforms, which are then dried at 45° C. and 45% relative humidity forabout 120 hours and dried for an additional 5 hours at 45° C. atotherwise ambient conditions.

[0123] The dosage forms are assayed for release of nefazodonehydrochloride in the assay described in Example 2. The release rates forfive individual dosage forms and the cumulative percent of dose releasedare represented in FIG. 7 and FIG. 8, respectively. The dosage formsexhibit a nominal T₉₀ of 15.1 hours and a mean release rate of 13.4mg/hr over a prolonged period of time, extending substantially frominterval 4 to interval 10. The dosage forms release nefazodonehydrochloride at a uniform release rate over a prolonged period of time.

EXAMPLE 5

[0124] Employing the general procedure of EXAMPLE 1 and proportionateamounts of materials (all percentages expressed as weight percentages),the following dosage form containing 300 mg nefazodone hydrochloride isprepared:

[0125] A drug layer having a weight of 435 mg consisting of 69%nefazodone hydrochloride, 20.24% polyethylene oxide (Polyox N-80), 5%hydroxypropyl cellulose (KIucel MF), 3% polyoxyl 40 stearate (MYRJ 52S),2% crospovidone (PVP XL), 0.75% stearic acid and 0.01% butylatedhydroxytoluene (BHT) is prepared. A push layer is prepared having aweight of 174 mg consisting of 64.1% polyethylene oxide (Polyox 303),30.0% sodium chloride, 5% hydroxypropyl methylcellulose (HPMC E-5), 0.5%red ferric oxide, 0.25% stearic acid and 0.08% BHT. The bilayer corecomprising the drug layer and the push layer is tableted as described.

[0126] Next, a subcoat is prepared with 70% Klucel EF and 30% povidoneK29-32 with ethanol as the solvent. After application, the amount of thesubcoat on the bilayer core is 31.4 mg. The semi-permeable membrane isprepared with 85% cellulose acetate 398-10 and 15% poloxamer (PluronicsF68) with a solvent system of 95% acetone and 5% water. The weight ofthe membrane on the subcoated bilayer core after application is 40.3 mg.

[0127] An orifice having a diameter of 175 mils is drilled in the dosageforms, which are then dried at 45° C. and 45% relative humidity forabout 120 hours and dried for an additional 5 hours at 45° C. atotherwise ambient conditions.

[0128] The dosage forms are assayed for release of nefazodonehydrochloride in the assay described in Example 2. The release rates forfive individual dosage forms and the cumulative percent of dose releasedare represented in FIG. 9 and FIG. 10, respectively. The dosage formsexhibit a nominal T₉₀ of 11.9 hours and a mean release rate of 26.7mg/hr over a prolonged period of time, extending substantially frominterval 4 to interval 10. The dosage forms release nefazodonehydrochloride at uniform rate of release over a prolonged period oftime.

EXAMPLE 6

[0129] Employing the general procedure of EXAMPLE 1 and proportionateamounts of materials (all percentages expressed as weight percentages),the following dosage form containing 400 mg nefazodone hydrochloride isprepared:

[0130] A drug layer having a weight of 580.0 mg consisting of 69%nefazodone hydrochloride, 20.24% polyethylene oxide (Polyox N-80), 5%hydroxypropyl cellulose (Klucel MF), 3% polyoxyl 40 stearate (MYRJ 52S),2% crospovidone (PVP XL), 0.75% stearic acid and 0.01% butylatedhydroxytoluene (BHT) is prepared. A push layer is prepared having aweight of 232.0 mg consisting of 64.1% polyethylene oxide (Polyox 303),30.0% sodium chloride, 5% hydroxypropyl methylcellulose (HPMC E-5), 0.5%red ferric oxide, 0.25% stearic acid and 0.08% BHT. The bilayer corecomprising the drug layer and the push layer is tableted as described.

[0131] Next, a subcoat is prepared with 70% Klucel EF and 30% povidoneK29-32 with ethanol as the solvent. After application, the amount of thesubcoat on the bilayer core is 36.3 mg. The semi-permeable membrane isprepared with 80% cellulose acetate 398-10 and 20% poloxamer F68 with asolvent system of 95% acetone and 5% water. The weight of the membranecoat on the subcoated bilayer core after application is 88.7 mg

[0132] An orifice having a diameter of 190 mils is drilled in the dosageforms, which are then dried at 45° C. and 45% relative humidity forabout 120 hours and dried for an additional 5 hours at 45° C. atotherwise ambient conditions.

[0133] The dosage forms are assayed for release of nefazodonehydrochloride in the assay described in Example 2. The release rates forfive individual dosage forms and the cumulative percent of dose releasedare represented in FIG. 11 and FIG. 12, respectively. The dosage formsexhibit a nominal T₉₀ of 14 hours and a mean release rate of 29.7 mg/hrover a prolonged period of time, extending substantially from interval 5to interval 13. The dosage forms uniformly release nefazodonehydrochloride over a prolonged period of time.

EXAMPLE 7

[0134] Representative samples of the dosage forms of this inventioncontaining 100-600 mg of nefazodone hydrochloride having orificediameters of 110-200 mils are orally administered to subjectsonce-a-day. Blood samples are drawn from the subjects at regularintervals (typically 1-4 hours) and the blood plasma samples so obtainedanalyzed for amounts of nefazodone hydrochloride present. The dosageforms of the invention provide sustained blood plasma levels of between5 ng/ml and 2500 ng/ml. Steady state blood plasma levels are maintainedat uniformly therapeutic levels such that quotient that is formed from[C_(max)—C_(min)]/C_(min) for nefazodone hydrochloride in plasma overthe 24-hour interval after administration is 3 or less.

[0135] Surprisingly, the flow-promoting wall 7 provides forsubstantially complete release, i.e. 80% or greater by weight, of drugfrom the dosage forms fabricated in accordance with this invention. Indosage forms in which there is high-drug loading, i.e., 40% or greateractive agent in the drug layer based on the overall weight of the druglayer, and in the absence of flow-promoting layer 7, it has beenobserved that significant residual amounts of drug may remain in adevice such as described herein after the period of delivery has beencompleted. In some instances without the flow promoting layer, amountsof greater than 20% remained in the device at the end of a twenty-fourhour period. Residual drug amounts were reduced by the addition of aninner coat of a hydroxyalkylcellulose applied to the drug layer. Whenthe inner coat comprised hydroxypropylcellulose (Klucel EF) having anumber average molecular weight of 80,000, the subcoat weights to obtain7%, 4% and 3% residual drug content, were, as a percentage of bilayercore weight, 9%, 12% and 15%, respectively. The flow-promoting layer orinner wall 7 reduces the frictional forces between the semipermeablewall 2 and the external surface of the drug layer, thus allowing formore complete delivery of drug from the device. Particularly in the caseof active compounds having a high cost, such an improvement presentssubstantial economic advantages since it is not necessary to load thedrug layer with an excess to insure that the minimal amount requiredwill be delivered.

EXAMPLE 8

[0136] Employing the general procedure of EXAMPLE 1, dosage formscontaining 400 mg of nefazodone hydrochloride, comprising 83% of thedrug layer weighing 482 mg, and having a 14.1 mg subcoat forming theflow promoting layer and 81.3 mg of the semipermeable membrane areprepared with an exit orifice of 155 mils in the end of the dosage form.Similarly, dosage forms containing the same amount of nefazodonehydrochloride and 83.7 mg of the semipermeable membrane and having anexit orifice of 155 mils on the end of the dosage form, but without asubcoat, are prepared. Representative dosage forms were tested in therelease rate assay, and the results are shown graphically in FIGS.13A-13D. Results for the subcoated dosage forms are shown in FIG. 13A,illustrating an average release rate of about 10.3 mg/hour that issubstantially zero order, and FIG. 13B, illustrating the cumulativerelease rate having a T₉₀ of about 26.6 hours. In contrast, the resultsfor the uncoated dosage form presented in FIGS. 13C and 13D illustrate avarying release rate with only about 55% of the drug released after 26hours. The dosage forms fabricated with the flow promoting layer appliedas a subcoat provide controlled release of the drug over a prolongedperiod of time with minimal residual drug remaining in the dosage form24 hours after administration.

[0137] The present invention comprises the following characteristics andfeatures, either alone or in combination with one or more of each other:

[0138] a dosage form for an active agent comprising a wall defining acavity, the wall having an exit orifice formed or formable therein andat least a portion of the wall being semipermeable, an expandable layerlocated within the cavity remote from the exit orifice and in fluidcommunication with the semipermeable portion of the wall, a drug layerlocated within the cavity adjacent the exit orifice and in direct orindirect contacting relationship with the expandable layer, and aflow-promoting layer interposed between the inner surface of the walland at least the external surface of the drug layer located within thecavity; the dosage form wherein the drug layer contains at least 40% byweight of drug based on the weight of the drug layer; the dosage formwherein the expandable layer comprises an osmotic agent;. the dosageform wherein the flow-promoting layer comprises a material selected fromhydrogels, gelatin, polyethylene oxides of less than 100,000 MW,hydroxyalkylcelluloses having number average molecular weights ofbetween 9,500 and 1,250,000, and hydroxyalkyl alkylcelluloses havingnumber average molecular weights of between 80,000 to 850,000, andmixtures thereof; the dosage form wherein the flow-promoting layer isadapted to facilitate release of at least 80% of the drug in the druglayer to the environment of use; an article of manufacture comprising acompressed drug composition overcoated with a flow-promoting layer; thearticle of manufacture comprising an expandable layer in direct orindirect contact with the drug composition and forming a bilayer corewith the drug composition, wherein the bilayer core is overcoated withthe flow-promoting layer; the article of manufacture wherein theflow-promoting layer comprises a material selected from hydrogels,gelatin, polyethylene oxides of less than 100,000 MW,hydroxyalkylcelluloses having number average molecular weights ofbetween 9,500 and 1,250,000, and hydroxyalkyl alkylcelluloses havingnumber average molecular weights of between 80,000 to 850,000, andmixtures thereof; and a method of facilitating the release of a drugfrom a dosage form comprising a compressed drug composition, asemipermeable wall and a push-layer, the method comprising interposing aflow-promoting layer between the semi-permeable wall and the compresseddrug composition.

[0139] The above-described exemplary embodiments are intended to beillustrative in all respects, rather than restrictive, of the presentinvention. Thus, the present invention is capable of implementation inmany variations and modifications that can be derived from thedescription herein by a person skilled in the art. All such variationsand modifications are considered to be within the scope and spirit ofthe present invention as defined by the following claims.

What is claimed is:
 1. A dosage form for an active agent comprising: awall defining a cavity, the wall having an exit orifice formed orformable therein and at least a portion of the wall being semipermeable;an expandable layer located within the cavity remote from the exitorifice and in fluid communication with the semipermeable portion of thewall; a drug layer located within the cavity adjacent the exit orificeand in direct or indirect contacting relationship with the expandablelayer; and a flow-promoting layer interposed between the inner surfaceof the wall and at least the external surface of the drug layer locatedwithin the cavity.
 2. The dosage form of claim I wherein the drug layercontains at least 40% by weight of drug based on the weight of the druglayer.
 3. The dosage form of claim 1 wherein the expandable layercomprises an osmotic agent.
 4. The dosage form of claim 3 wherein theflow-promoting layer comprises a material selected from hydrogels,gelatin, polyethylene oxides of less than 100,000 MW,hydroxyalkylcelluloses having number average molecular weights ofbetween 9,500 and 1,250,000, and hydroxyalkyl alkylcelluloses havingnumber average molecular weights of between 80,000 to 850,000, andmixtures thereof.
 5. The dosage form of claim 1 wherein theflow-promoting layer is adapted to facilitate release of at least 80% ofthe drug in the drug layer to the environment of use.
 6. An article ofmanufacture comprising a compressed drug composition overcoated with aflow-promoting layer.
 7. The article of claim 6 comprising an expandablelayer in direct or indirect contact with the drug composition andforming a bilayer core with the drug composition, the bilayer core beingovercoated with the flow-promoting layer.
 8. The article of claim 7wherein the flow-promoting layer comprises a material selected fromhydrogels, gelatin, polyethylene oxides of less than 100,000 MW,hydroxyalkylcelluloses having number average molecular weights ofbetween 9,500 and 1,250,000, and hydroxyalkyl alkylcelluloses havingnumber average molecular weights of between 80,000 to 850,000, andmixtures thereof.
 9. The article of claim 7 wherein the flow-promotinglayer comprises an hydroxypropyl cellulose.
 10. A method of facilitatingthe release of a drug from a dosage form comprising a compressed drugcomposition, a semipermeable wall and a push layer, the methodcomprising interposing a flow promoting layer between the semipermeablewall and the compressed drug composition.
 11. The method of claim 10wherein the flow promoting layer comprises a coating on the compresseddrug composition prepared from a hydroxyalky cellulose and a loweralkanol.